11-64807557-G-C

Position:

• chr11-64807557-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Strong

The NM_001370259.2(MEN1):​c.778C>G​(p.Gln260Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q260P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.67

Genes affected

MEN1 (HGNC:7010): (menin 1) This gene encodes menin, a tumor suppressor associated with a syndrome known as multiple endocrine neoplasia type 1. Menin is a scaffold protein that functions in histone modification and epigenetic gene regulation. It is thought to regulate several pathways and processes by altering chromatin structure through the modification of histones. [provided by RefSeq, May 2019]

MEN1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64807556-T-G is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MEN1. . Trascript score misZ 4.1921 (greater than threshold 3.09). GenCC has associacion of gene with multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.778C>G	p.Gln260Glu	missense_variant	4/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.778C>G	p.Gln260Glu	missense_variant	4/10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 27, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MEN1 protein function. This variant has not been reported in the literature in individuals with MEN1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with glutamic acid at codon 260 of the MEN1 protein (p.Gln260Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;D;D;D;D;D;.;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.;.;D;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;M;M;M;M;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.5	N;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D;D;D;.;D;D
Polyphen		0.95, 0.99, 1.0	.;P;D;D;D;D;D;D;D;.;.;.
Vest4		0.79
MutPred		0.88		.;.;.;.;.;Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);.;.;.;
MVP		0.97
MPC		2.3
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.93
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64575029;